In a drug discrimination paradigm pigeons and rats were trained with an operant procedure to discriminate between the presence and absence of the effects of delta 9-THC (1.0 and 3.0 mg/kg, injected IM 90 min and I.P. 30 min before the start of the session). Once trained, various THC metabolites as well as a water-soluble derivative of THC (SP-111), were substituted for delta 9-THC to test for generalization to the training drug. Generalization to delta 9-THC occurred with the 11-hydroxy metabolites and the potency order was 11-OH-delta 9-THC > 11-OH-delta 8-THC greater than or equal to delta 9-THC. Among the other metabolites tested (8 alpha-OH-delta 9-THC, 8 alpha, 11-di-OH-delta 9-THC, 8 beta-OH-delta 9-THC, 8 beta, 11-di-OH-delta 9-THC), it was only 11-di-OH-delta 9-THC that completely substituted for delta 9-THC in pigeons, albeit at very high dose levels (rats were not tested with these metabolites). SP-111 generalized to delta 9-THC in both species. However, the onset of action of SP-111 was slower than that for delta 9-THC, especially in pigeons. These studies show the importance of obtaining complete dose-effect determinations over time when assessing structure-activity relationships with drug-discrimination procedures.